The purpose of this Medication Development Research Center grant is to systematically and comprehensively test different potentially therapeutic drugs using human laboratory models of drug abuse for opiates, cocaine and cigarette smoking. This center grant will also examine how the results from human laboratory models will generalize to an outpatient clinical setting. Four individual projects and three Cores have been submitted. The first project focuses on the effects of dynorphin A (1- 13), an endogenous opiate, in opiate abusers. The proposed studies examine the effects of dynorphin on heroin withdrawal, the effects of dynorphin on the self-administration of opiates, the interaction of dynorphin and morphine in opiate-naive and opiate-dependent subjects, and the self-administration of dynorphin. The second project examines the effects of ritanserin, a 5-HT2 antagonist, and nifedipine, a calcium channel inhibitor, as potential pharmacological agents in the treatment of cocaine abusers. Studies will be conducted to determine the effects of these medications on human laboratory models of cocaine self- administration, relapse and withdrawal. The third project will examine the effects of ritanserin using an outpatient clinical setting in female cocaine abusers who do or do not have a current history of affective disorder. Studies will be conducted to examine the effects of ritanserin on cocaine self-administration and relapse to cocaine. The fourth project examines the role of a metabolite of nicotine, cotinine, in tobacco dependence. The proposed studies will examine the effects of cotinine during cigarette abstinence, physical dependence of cotinine, the self-administration of cotinine, and the effects of cotinine on cigarette smoking. The strengths of this application include 1) the testing of novel compounds as potential medications, 2) the use of parallel designs and methodologies across drugs, 3) the extension of laboratory findings to an outpatient setting, 4) the presence of ongoing clinical research programs and funded grants in these areas among the investigators, and 5) well established collaborations among the investigators, and 6) the integration of the proposed clinical studies with strong preclinical and basic research programs in drug abuse, and a drug abuse training grant, at the University of Minnesota. All four studies will use the services provided by the three proposed Administrative and Support, Analytical and Statistical Cores.